1. Field of the Invention
This invention relates to the treatment of histiocytosis, and more particularly to a method for treating histiocytosis that utilizes a 2-halo-2'-deoxyadenosine.
2. Description of Related Art Histiocytes and lymphocytes, the key constituents in lesions of the histiocytosis syndromes, show an enormous capacity for metamorphosis, functional change, secretion of cytokines, and interaction with one another and other cells, especially endothelial cells. For instance, histiocytes and lymphocytes may be either "down" or "up" regulated by certain "activators" causing them to secrete some cytokines, to stop secreting other cytokines, to proliferate, phagocytize, transform, etc.--a complex paradigm referred to as "activation."
Histiocytes are bone marrow derived cells of the mononuclear phagocytic system (MPS) and dendritic cells that are possibly a subset of the MPS. Histiocytes are known to be extremely dynamic and their morphologic and immunologic traits are capricious; to a large degree that capriciousness is influenced by their interaction with other cells, particularly lymphocytes, and by biological response modifiers or cytokines.
Normal Langerhans cells and Langerhans cell histiocytosis (LCH) cells are dendritic cells that have cytological, functional and ultrastructural characteristics shared by other histiocytes, but they are unique in that they contain Langerhans cell granules (M. S. Birbeck et al, J. Invest. Dermatol. 37:51-64, 1961). It is believed by some that LCH cells are not derived from normal Langerhans cells at all, but they could stem from circulating dendritic cells or even ordinary histiocytes that have, under pathological conditions, acquired characteristic markers of Langerhans cells (B. E. Favara et al, Hematol./Oncol. Clin. No. Amer., 1:75-96, 1987; J. S. Greenberger et al, Medicine, 1:311,338, 1981; M. E. Osband et al., New Eng. J. Med., 304:146-153, 1981). Others believe that Langerhans-cell histiocytosis results from the proliferation and accumulation of tissue histiocytes. There is not a great depth of knowledge in the art about the origin of some histiocytes (Favara et al., Leukemia and Lymphoma, 2:141-150, 1990).
Histiocytosis is clinically manifested as osteolytic lesions, hypothalamic insufficiency, and seborrheic and vesiculopustular lesions on the scalp, perineum, rectum, and vulva (J. E. Groopman et al, Ann Intern Meal. 94.:95-107, 1981). Heretofore, treatment has been largely palliative and includes corticosteroids, alkylating agents, antimetabolites, vinca alkaloids, and irradiation (D. M. Komp, Semin Oncol. 18:18-23, 1991 ). Combination chemotherapy offers no advantage over the use of single agents and is associated with greater toxicity. 2-Chlorodeoxyadenosine (2-CdA) (cladribine, Leustatin Ortho Biotech, Raritan, N.J.!), a purine analog with activity in indolent lymphoproliferative disorders and myeloid leukemias (A. Saven et al, N. Engl. J. Med. 330:691-697, 1994; A. Saven et al., Ann. Intern. Med., 120:784-91, 1994) is potently toxic to monocytes in vitro.
2-Halo-2'-deoxyadenosines have been reported to be useful in treating non-tumor diseases categorized as monocyte mediated diseases. For instance, PCT patent application number PCT US89/01088, published on 9/21/89, discloses that diseases resulting from chronically infected monocytes and inflammatory diseases resulting from autoimmune disorders caused by monocytes, such as rheumatoid arthritis, can be treated with 2-CdA, which exhibits potent cytotoxicity toward monocytes. U.S. Pat. No. 5, 106,837, issued Apr. 21, 1992 discloses additional monocyte mediated diseases that respond to treatment with 2-CdA: hemolytic anemia, Chagas disease, Leishmaniasis, toxoplasmosis, malaria, pneumocystis sarcoidosis, chronic granulomatous hepatitis, Wegener's granulomatosis, Paget's disease, atherosclerosis, inflammatory bowel disease, and granulomatous uveitis. Treatment of multiple sclerosis with 2CdA is additionally disclosed in U.S. Pat. No. 5,310,732 published Sept. 2, 1993.
In those disclosures, the 2-halo-2'-deoxyadenosine was described as acting primarily against monocytes. The 2-halo-2'-deoxyadenosine used in those studies was 2-chloro-2'-deoxyadenosine (2-CdA), which was used at a dosage of 0.1 mg/kg body weight/day administered by infusion over a five-day time period with courses at about monthly intervals for a total of three courses of treatment. Patient monocyte levels dropped substantially to zero during treatment cycles and rose to about pretreatment levels about ten days after 2-CdA infusion was stopped. Patients showed improvement in various assays for rheumatoid arthritis during the treatment. Follow-up letters from personal physicians to one of those inventors, Dr. Carson, indicated a white cell count at about 50 percent of pretreatment values that lasted for one to three years after treatment ceased. Those personal physicians also reported greater patient improvements that became evident several months after cessation of treatment.
The teachings of the art contain a single reference to treatment of histiocytosis with a 2-chlorodeoxyadenosine. Saven et al., New England Journal of Medicine, 329: 734-735, 1993, reported that 2-CdA when administered to a patient with symptoms histologically consistent with a diagnosis of Langerhans-cell histiocytosis, sometimes referred to as histiocytosis X (a Class I histiocytosis) was successfully treated with 2-Cda. A 33 year old woman, who had been treated with high-dose steroid therapy and vinblastine, oral etoposide, vincristine, cyclophosphamide, and methotrexate over a two year period, was administered four courses of 2-Cda at 0.1 mg per kilogram of body weight per day for 7 days by continuous intravenous infusion at intervals of 28 to 35 days, except that the second course was delayed by development of dermatomal herpes zoster and later complicated by transient grade 3 neutropenia. The patient had experienced complete remission for more than 17 months at the time of the report.
The toxicity of CdA to monocytes and lymphocytes has also been reported by Carrera et al., J. Clin. Invest., 86:1480-1488 (1990). That paper also disclosed the use of CdA in clinical trials in patients having chronic lymphoid malignancies. Toxicity in vitro of CdA and 2-fluorodeoxyadenosine (FdA) toward resting and proliferating lymphocytes had been reported by the same research group in Carson et al., Proc. Natl. Acad. Sci., USA, 79:3848-3852 (1982). Priebe et al., Cancer Res., 48:4799-4800 (1988) reported that CdA elevated in vivo NK cell activity at concentrations (6-25 mg/kg/day) that inhibited T-dependent and T-independent antibody responses in mice.
Carson et al., Blood, 62(4):737-743 (1983) reported on the in vitro effects of CdA on a variety of cells and cell lines including resting normal T lymphocytes, slowly dividing malignant T cells from a patient with mycosis fungoides and CCRF-CEM malignant T lymphoblasts. A time- and concentration-dependent relation for CdA cytotoxicity was reported, with the malignant T lymphoblasts being more sensitive to CdA than were resting normal T lymphocytes.
Carson et al., Proc. Natl. Acad. Sci, USA, 81:2232-2236 (1984) and Piro et al., Blood, 72:1069-1073 (1988) also reported on the positive effect of CdA on various human lymphocytic neoplastic disorders, including chronic lymphocytic leukemia (CLL), and had previously reported that CdA was an effective agent for treating the murine B cell L1210 lymphoid leukemia in vivo. Carson et al., Blood, 62:737-743 (1983).
The Piro et al., Blood, 72:1069-1073 (1988) studies with CLL illustrated some partial responses (4/18) and other clinical improvements (6/18), but no complete responses. Those workers also reported that in vitro studies of the sensitivity of patient CLL cells to CdA did not correlate with in vivo findings. Other in vitro studies indicated that T cells were more vulnerable than B cells to CdA, but that difference was not clinically apparent. Saven et al., N. Engl. J. Med., 330(10):691-697 (1994).
Avery et al., Cancer Res., 49:4972-4978 (1989) also reported the effects of CdA on T-lymphoblastic, B-lymphoblastic and non-T, non-B cell lines, as well as in vivo effects on mice inoculated with L1210 leukemia of 2-bromo-2'-deoxyadenosine (BrdA) at 11.25 mg/kg/injection alone and paired with other therapeutic agents. Saven and Piro, N. Engl. J. Med., 330(10):691-697 (1994) reported on the use of CdA and 2'-deoxycofurmycin in treating hairy cell leukemia, a B cell neoplasm.
Parsons et al., Biochem. Pharmacol,, 35:660-665 (1986) reported results with two human melanoma cell lines that were sensitive to each of CdA, FdA and BrdA. Saven et al., J. Clin. Oncol., 11(4):671-678 (1993) noted that because of the interferon-sensitivity of hairy cells and the sensitivity of those cells to CdA, melanoma and renal cell carcinoma that are also sensitive to interferon might be similarly sensitive to CdA in vivo, as were the two melanoma cell lines reported by Parsons et al. sensitive in vitro. The results of the above Saven et al. CdA studies with human patients with melanoma (nine patients) and renal cell carcinomas (two patients) showed no responses to the treatment. Contrarily, two of seven patients with astrocytomas, a tumor not noted to be sensitive to interferon, showed marked improvement. Thus, the attempted parallel between tumor cell interferon-sensitivity and successful treatment with CdA was not evident from those studies. In addition, the in vitro sensitivity of the assayed melanoma cell lines to CdA was not observed in vivo, in a clinical setting.
Reiter et al., Purine and Pyrimidine Metabolism in Man VII, Part A, Harness et al., eds., Academic Press, New York (1991) pages 69-73 reported on the combined use of interferon-.alpha. (IFN-.alpha.) and CdA upon various tumor cell lines including a hairy cell leukemia-like cell line, (Eskol 17), a cervical carcinoma cell line, a chronic myelogenous leukemia cell line and an AIDS-related Kaposi's sarcoma. They reported an additive time- and dose-dependent effect on cell growth, but no synergy between the two treating agents. Those workers also reported that CdA did not affect NK cell-mediated cytotoxicity of Eskol 17 cells in the presence or absence of IFN-.alpha.. Although CdA neither affected the activity of NK cells nor was involved in the priming of NK cells by IFN-.alpha., CdA was reported to affect the target tumor cells.
Beutler et al., Leukemia and Lymphoma, 5:1-8 (1991) reported that CdA treatment provided mixed results in patients with T cell lymphomas that were resistant to conventional therapies. Here, of the evaluable patients, some had complete remissions (3/17), some had partial remissions (5/17) and more than half had no response (9/17). This paper also reported results with low grade as well as high and intermediate grades of non-Hodgkin's lymphomas. For the low grade disease, just under 40 percent of the evaluable patients (15/40) exhibited a complete or partial response, and the remainder exhibited no response (25/40). Somewhat poorer results were found for patients with intermediate or high grade diseases; 7/26 complete or partial response and 9/26 no response. Results with other hematologic disorders involving fewer patients were also reported.
Petzer et al., Blood, 78(10):2583-2587 (1991) reported the effects CdA on various progenitor cells from bone marrow, including so-called T lymphocyte colony forming cells (CFU-TL). Those authors reported a dose-dependent inhibition of the growth of CFU-TL in vitro, and also reported that the drug concentration needed for complete inhibition much higher than that required for erythroid and granulocyte/macrophage progenitors. Those authors commented that the more mature the treated colony forming cells were, the higher the CdA concentration that was needed to inhibit proliferation. They also noted that the assay they used probably does not detect the true T lymphocyte progenitor, and that their assay may not accurately reflect regulatory mechanisms in vivo.
It is thus seen that the effects of a 2-halo-2'-deoxyadenine upon tumor growth are not yet predictable as to which tumors are sensitive, although once activity for one compound is found, the other 2-halo-dA's also possess that activity; that in vitro studies may not correlate with in vivo, patient studies; and that the effects of a drug from this group such as CdA upon a tumor cell type can vary widely from patient to patient even where a positive inhibition of growth is found.
Other studies, Montgomery et al., J. Am. Chem. Soc., 82:463-468 (1959), indicated that 2-fluoroadenosine exhibits a relatively high degree of cytotoxicity. Those workers reported that C57 black mice implanted with Adenocarcinoma 755 (Ad755) could tolerate only about 1 milligram per kilogram of body weight. 2-Fluoroadenosine was found to be inactive at that level against Ad755 as well as leukemia L1210 and the Erlich ascites tumor.
Hence, the need exists for new and improved methods of treating histiocytosis utilizing in vivo administration of a 2-halo-2'-deoxyadenosine as the active agent.